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The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins

¹ The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia
² Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3010, Australia

Correspondence to Philippe Bouillet: bouillet{at}wehi.edu.au

Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly. As numerous in vitro studies have not resolved this issue, we have investigated Bim's activity in vivo by a genetic approach. Because the BH3 domain determines binding specificity for Bcl-2 relatives, we generated mice having the Bim BH3 domain replaced by that of Bad, Noxa, or Puma. The mutants bound the expected subsets of prosurvival relatives but lost interaction with Bax. Analysis of the mice showed that Bim's proapoptotic activity is not solely caused by its ability to engage its prosurvival relatives or solely to its binding to Bax. Thus, initiation of apoptosis in vivo appears to require features of both models.

© 2009 Mérino et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

O.M. Siggs' present address is Dept. of Genetics, The Scripps Research Institute, La Jolla, CA 92037.

Abbreviations used in this paper: MOMP, mitochondrial outer membrane permeabilization; PKD, polycystic kidney disease; tBid, truncated Bid; WBC, white blood cell; WT, wild type.

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This article has been cited by other articles:

• Hubner, A., Cavanagh-Kyros, J., Rincon, M., Flavell, R. A., Davis, R. J. (2010). Functional Cooperation of the Proapoptotic Bcl2 Family Proteins Bmf and Bim In Vivo. Mol. Cell. Biol. 30: 98-105 [Abstract] [Full Text]  
• Merino, D., Giam, M., Hughes, P. D., Siggs, O. M., Heger, K., O'Reilly, L. A., Adams, J. M., Strasser, A., Lee, E. F., Fairlie, W. D., Bouillet, P. (2009). The role of BH3-only protein Bim extends beyond inhibiting Bcl-2-like prosurvival proteins. JEM 206: i19-i19 [Full Text]  
• Leslie, M. (2009). Both routes to cell death necessary. JCB 186: 300-300 [Full Text]  

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